摘要:背景 腎移植後常合併多重免疫抑制劑,利用協同作用以增加療效,減少藥品個別的劑量以降低劑量相關的副作用。通常包括 calcineurin inhibitors (CNIs: cyclosporine 或tacrolimus)、antimetabolites (mycophenolate或 azathioprine)、mTOR inhibitors (everolimus或 sirolimus) 和類固醇。由於CNIs和mTOR inhibitors都是CYP3A和P-glycoprotein (P-gp) 的受質,當它們併用時可能會互相競爭這些代謝途徑而影響血中濃度;且 CNIs會抑制CYP3A,cyclosproine更是很強的 P-gp抑制劑。 使用含有 everolimus的治療方案時,各藥品的藥動學 (PK) 是否會改變,臨床療效是否受影響,仍有待評估。目前已知 mycophenolate mofetil (MM)F合併 tacrolimus時,不影響 tacrolimus的 PK,故以MMF做為對照來探討 everolimus對 tacrolimus PK的影響。 目的 了解 everolimus 對 tacrolimus PK的影響。 方法 此為前瞻性、隨機分配、開放式的研究。納入臺大醫院第一次腎臟移植、年齡為 20 - 65歲、AST/ALT 都在正常範圍最大值兩倍內之病人;排除懷孕、肺結核、HBV或 HCV帶原者、HIV (+)、再移植或多重器官移植、有類風濕關節炎病史、試驗前或試驗期間使用 CYP3A或 P-gp誘導劑或抑制劑的病人。在取得納入病人同意書後,隨機分成everolimus/tacrolimus/corticosteroids跟 MMF/tacrolimus/corticosteroids兩組。 兩組病人之corticosteroid與 tacrolimus療程劑量均遵守醫院標準療程,tacrolimus 0.1- 0.15 mg/kg/day po q12h自開刀後一天 (POD1) 開始使用,標的谷濃度 (Ctrough) 為 8 - 12 ng/mL。Everolimus/tacrolimus/corticosteroids組的病人另自 POD1開始使用 everolimus 1 mg po q12h,Ctrough為 3 - 8 ng/mL。MMF/tacrolimus/corticosteroids組則以 MMF 10 - 15 mg/kg po q12h代替 everolimus。Everolims、tacrolimus血中濃度、肝腎功能、血球數等需密切監測,以確保藥品療效與安全。 當 tacrolimus 與 everolimus血中濃度達到穩定狀態後,分別在給藥前、給藥後 1、2、3、5、8小時抽血,利用 Win-Nonlin non-compartment model得到 tacrolimus、everolimus的 PK參數,以探討 everolimus對 tacrolimus PK的影響。
Abstract: Background Multidrug immunosuppression regimens have potential synergistic effects which allow the use of lower doses of individual agents and may therefore reduce the dose-related adverse effects. These regimens generally include individual drugs from two or three of the following classes: calcineurin inhibitors (CNIs: cyclosporine or tacrolimus), antimetabolites (mycophenolate or azathioprine), mammalian target of rapamycin (mTOR inhibitors: everolimus or sirolimus), and corticosteroids. CNIs and mTOR inhibitors are substrates for CYP3A4 and P-glycoprotein (P-gp); in addition, CNIs are inhibitors of CYP3A4 and P-gp. Therefore, concomitant administration of those drugs may alter their serum levels. It is remained to be evaluated whether the pharmacokinetics or clinical efficacy of tacrolimus will be affected when the regimens contain both everolimus and tacrolimus. Mycophenolate mofetil (MMF) has no effect on pharmacokinetics of tacrolimus; therefore, MMF can be used as a control to understand the effects of everolimus on the pharmacokinetics of tacrolimus in kidney transplant patients. Purpose To understand the effects of everolimus on the pharmacokinetics of tacrolimus in Taiwanese kidney transplants patients in order to design an optimal everolimus/tacrolimus combination regimen. Method This is a prospective, randomized, open-label, parallel-group trial. Patients who undergo first kidney transplantation at National Taiwan University Hospital, at the age of 20 to 65 years old, AST/ALT within 2 times of the upper normal limit will be included. The exclusion criteria are: pregnancy, TB, HBV or HCV carrier, HIV (+), re-transplant, multi-organ transplant, rheumatoid arthritis history, use of CYP3A or P-gp inhibitor or inducer agent before or after transplantation. After signing the informed consent, patients will be randomly assigned to triple therapy with everolimus or MMF in combination with tacrolimus and corticosteroids, i.e., everolimus/tacrolimus/corticosteroids or MMF/tacrolimus/corticosteroids group. The use of corticosteroids and Tacrolimus will follow the standard protocol in the hospital. Tacrolimus 0.1- 0.15 mg/kg/day po q12h will be started from post-operation day (POD) 1, with a target trough concentration (Ctrough) of 8 - 12 ng/mL. In Everolimus/ tacrolimus /corticosteroids group, everolimus 1 mg po q12h will be started from POD, with a target Ctrough of 3 - 8 ng/mL. In the MMF/tacrolimus/corticosteroids group, MMF 10 - 15 mg/kg po q12h will be used instead of everolimus. Everolims and tacrolimus serum concentration, kidney and hepatic function, blood counts, etc. will be closely monitored to ensure effectiveness and safety of drug therapy. The whole blood sample will be collected before dosing and at 1, 2, 3, 5, and 8 hours after the tacrolimus and everolimus dose is administrated when steady state being achieved. Win-Nonlin non-compartment model will be used to calculate pharmacokinetic parameters of tacrolimus and everolimus in order to explore the differences between groups.